Aging of the skin is the most prominent feature of the aging process, being caused by multiple factors such as intrinsic aging process and UV light exposure. Age-related dermal disorders include for example dermal atrophy, actinic keratosis, pseudoscars, lentigines, focal areas of dermal thickening, and coarse wrinkles.
Dermal atrophy, also called skin atrophy or atrophy, is a disorder manifesting thinning or depression of skin due to reduction of underlying tissue. Dermal atrophy is a major clinical problem in the elderly population. Loss of dermal integrity leads to increased fragility of the skin and precludes the use of intravenous lines in many cases. Impairment in wound healing is an important clinical sequelae of reduced dermal integrity leading to an increase in the number of the infections and complications following injury. Pseudoscars are stellate lesions that occur spontaneously in elderly individuals which can occur as senile and presenile forms. These lesions can be found in 20% of patients over the age of 70. Lentigines (or liver spots) are areas of hyperpigmentation occurring with age and may represent precursor lesions to lentigo maligna and melanoma. They may increase with age and become common in middle aged and elderly individuals. Seborrheic or actinic keratosis, which comprise focal areas of epidermal thickening, can occur, possibly representing a response to damage. Similarly, coarse wrinkles are thought to arise from a damage response. Currently, treatments for age-related dermal atrophy and related disorders include subdermal hyaluronic acid injection, injection of botulinum toxin or topical application of antioxidant such as vitamin C, green tea extract, and coenzyme Q, but these agents are not able to fully treat these conditions.
Cellular senescence is a stress response activated by mammalian cells upon exposure to several insults, such as oxidative stress, genotoxic stress, telomere attrition, or dysregulated mitogenic signaling. These stresses activate the senescence response by triggering two pathways: the p53/p21CIP1/WAF1 and the p16INK4A/Rb pathway, which are required to establish and maintain the senescence response. Senescence-inducing stimuli can cause DNA damage and trigger a sustained DNA damage response (DDR): in response to sustained, unresolved DNA damage, the Ataxia Telangiectasia Mutant (ATM) kinase activates p53 and its transcriptional target p21CIP1/WAF1, which arrests cellular proliferation by inhibiting cell-cycle-dependent kinases. In addition, the same senescence-inducing stimuli can trigger the activation of the Stress-Activated Protein Kinase p38 MAPK independently of DNA damage. p38 MAPK then can promote the arrest of the cell-cycle and establish senescence by activating the transcription factor HBP1, which increases the expression of p16INK4A. These two pathways seem to establish senescence with different kinetics: the DDR pathway usually mediate the initial arrest by increasing the levels of p21CIP1/WAF1, and only at later times senescence is reinforced by expression of p16INK4A. Furthermore, the p53 and the p38 MAPK pathways appear to be mostly independent of one another and are thus redundant, even though cross-talk between them may exist.
Mammalian/mechanistic target of rapamycin (mTOR) is an intracellular protein complex that is responsive to both growth factors and nutrient availability, and which also impacts mitochondrial function. It is comprised of the TOR kinase (originally identified in yeast, and known as mTOR in mammals), accessory proteins, and downstream mediators including the ribosomal S6 kinase (p70S6K) a key downstream target of TOR. The TOR signaling pathway is highly conserved in eukaryotes and is functionally defined as the target of the highly-specific antifungal, rapamycin.
The proteins that comprise the core mTOR complex are the ser-thr kinase mTOR, also known as the FKBP-12-rapamycin associated protein (FRAP1), and mammalian lethal with SEC 13 protein 8 (mLST8). These core components have the capability of forming either of two complexes, mTORC1 or mTORC2, which are distinguishable by their sensitivity to rapamycin. The rapamycin-sensitive mTORC1 contains the scaffolding protein regulatory-associated protein of mTOR (Raptor), whereas the rapamycin-insensitive complex mTORC2 contains the scaffolding protein rapamycin-insensitive companion of mTOR (Rictor). These scaffolding proteins function to direct mTORC1 and mTORC2 to their respective targets. Additional components are unique to each complex. For example, proline-rich Akt/PKB substrate 40 KDa (PRAS40) is an inhibitory protein associated with mTORC1, whereas the stress-activated MAP kinase-interacting protein 1 (Sin1) and the protein observed with Rictor-1 (proctor) protein are associated with mTORC2. The primary function attributed to the mTOR complex is the promotion of cell proliferation and growth of cells.
There is thus a need in the art for novel compositions and methods that can be used to treat or prevent certain age-related dermal conditions in a mammalian subject in need thereof, such as a human. The present invention fulfills this need.